This application proposes an investigation of a putative endophenotype and candidate genetic variant for cannabis abuse and dependence. A growing body of literature suggests that psychological reactions to the acute effects of marijuana may differ between frequent and infrequent cannabis users. The purpose of the proposed study is to build upon this body of research by investigating the relationship between frequency of marijuana use and subjective reactions to the acute effects of marijuana. A promising candidate genetic locus, the CNR1 SNP, rs2023239, will also be examined, with respect to its relationship to the endophenotype of differential subjective reaction and to its functional significance. Frequent and infrequent cannabis users will be recruited to examine: 1) whether a significant between-group difference in psychological reaction to an acute marijuana administration episode exists, such that frequent users report more positive and fewer negative psychological reactions; 2) whether the effect of the SNP on subjective reaction mediates its effect on frequency of cannabis use; and 3) what the functional significance of the CNR1 SNP is with respect to the function of the cannabinoid receptor gene. Findings will contribute to the development of an endophenotype of cannabis use-related psychopathology. As discussed in the application, problem use of marijuana presents a growing public health problem. Marijuana is the most commonly used illicit drug in the United States and most of the world, and a growing percentage of users now report difficulties in controlling their marijuana use. The proposed research will aid treatment of problem marijuana use by attempting to identify genetic and behavioral markers that make people more likely to develop cannabis abuse or dependence. Knowledge of these markers will allow health care providers to create targeted interventions to treat these disorders. [unreadable] [unreadable] [unreadable]